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Antibiotics - Coggle Diagram

- - - - Not necessarily killing
  - - - Biocides that destrpy or inhibit growth of microorganisms in or on living tissue
        
        e.g. hand-washes and surgical scrubs
    - - Biocides that destroy or inhibit growth of microorganisms on inanimate objects or surfaces
  - - - Post-antibiotic era
      - Emergence is always 'when' and not 'if'
      - Can be lost but typically slow + determinants may persist within populations
- - - - Target may not be relevant in a particular physiological state
    - - Adequate diagnosis + prescription choice
  - - - 80% antibiotics used in industrial animal agriculture
      - Mostly given routinely to healthy animals as a preventative measure rather than treatment
- - - - Transcription
      - DNA gyrase
    - - Drug efflux by membrane transporters is common resistance problem
    - - e.g. isoniazid and ethionamide for TB
      - Non-toxic when delivered to organism
        
        Metabolism within organism produces toxic effects
      - Arise through different activation pathways
        
        No cross resistance
      - Loss of enzyme = resistance
  - - - Inhibit bacterial DNA-dependent RNApol
      - e.g. rifampicin
      - RIF binds to \(\beta\) subunit (RpoB gene)
        
        Responsible for
        
        DNA + RNA binding
        
        RNA synthesis
        
        NTP binding
        
        RMP binding
        
        \(\sigma\) binding
        
        Binding blocks RNA elongation
        
        Blocks path once 2-3nt long
      - Core enzyme = \(\alpha_2\beta\beta'\omega\)
      - Activity spectrum
        
        Against gram-positive and gram-negative bacteria
        
        Very potent broad spectrum
        
        Very lipophilic
        
        Affects tissue + cell penetration
      - Don't block RNApol assembly or RpoB site activity
        
        Blocks channel containing DNA + growing RNA
        
        Blocks exit from RNApol
      - Resistance
        
        Rare mechanism
        
        Acquisition of enzymes to chemically modify RIF into inactive forms
        
        e.g. ADP-ribosylation
        
        Can't bind active site
        
        High frequency mutations
        
        RpoB mutations into insensitive forms
        
        Alter amino acids in RpoB 'hotspots'
        
        Examples
        
        S531L disorders RIF binding interface
        
        Reduced affinity
        
        ~40% of TB RIF resistance
        
        H526Y reshpaes binding pocket
        
        Blocks RIF binding
        
        D516Y changes charge density in RIF binding site
        
        Reduced affinity
    - - Binds similar site on RpoB
      - Also blocks RNA elongation at 2-4 nt stage
      - Resistance
        
        Altered amino acids RpoB 'hotspots'
        
        Partial cross resistance with Rif\(^R\)